Sequential induction of mitotic catastrophe followed by apoptosis in human leukemia MOLT4 cells by imidazoacridinone C-1311

Abstract

Imidazoacridinone C-1311 is a DNA-targeting antitumor intercalator/alkylator currently undergoing Phase II clinical trials. Here, we elucidated the sequence of death responses to C-1311 in human leukemia MOLT4 cells using drug concentration (30 nM) that causes near complete cell growth inhibition at 48 h. Early (6-12 h) responses included transient accumulation of cells at the G2/M border followed by also transient rise in several mitotic markers. Mitotic attempts were largely abnormal, resulting in numerous multinucleated cells (peaking at 24-39 h and declining markedly at later times). These events, indicative of mitotic catastrophe, were not associated with immediate cell death. The fraction of necrotic cells did not exceed 3%. Also, the classical manifestations of apoptosis were marginal at 24 h and their progression clearly followed the decline in the fraction of mitotic and multinucleated cells. Quantification of several apoptotic markers (including phosphatidylserine externalization, apoptotic DNA breaks, mitochondrial dysfunction, caspase activation, and cell membrane integrity) showed a considerable progression and the shift from early to late apoptosis at later times. At 72 h, >80% of cells were apoptotic. Collectively, these findings show that C-1311-induced mitotic catastrophe is not the ultimate death event but rather a step precipitating delayed, albeit massive, apoptotic responses.

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

“…In ovarian and osteogenic sarcoma cells, G 2 arrest resulted in a low level of apoptosis [20] , while in the human colon carcinoma HT-29 cell line, drug-treated cells progressed into mitosis after initial arrest in G 2 but were unable to undergo cytokinesis and died in a process resembling mitotic catastrophe [21] . Likewise, the treatment of human leukemia MOLT4 cells with C-1311 resulted in mitotic catastrophe, leading to a massive apoptotic response [22] . Taking these aspects of the mode of action of C-1311 into account, namely, metabolism and cell death, we examined the metabolism of this drug in an in vitro CHO cell model (previously, the metabolism of C-1311 was only investigated in cellfree systems), and we focused on the role of cytochrome P450 in the cellular response following drug treatment.…”

Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

“…It was evaluated in phase I clinical trials in patients with advanced solid tumors (Thomas et al, 2008;Isambert et al, 2010) and was effective in a phase II clinical trial in women with metastatic breast cancer . Despite their clinical potential, the biologic and biochemical mechanisms of C-1305 and C-1311 action are still under extensive study (Mazerska et al, 2001(Mazerska et al, , 2003Augustin et al, 2006;Skwarska et al, 2007). Both compounds intercalate to DNA and inhibit topoisomerase II activity (Skladanowski et al, 1996;Dziegielewski et al, 2002;Lemke et al, 2004;Koba and Konopa, 2007).…”

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

“…Castedo et al proposed this process to be different from apoptosis mode of cell death resulting from cell cycle checkpoint deficiencies and cellular damage (9). On the contrary, others have claimed that MC should be considered an aberrant mitosis that promotes autophagy (10) and/or leads to cell death through apoptosis, or necrosis (11,12). In spite of many discrepancies, it is believed that p53-deficient cells are particularly susceptible to MC.…”